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Test ID: TTRX Amyloidosis, Transthyretin-Associated Familial, Reflex, Blood

Reporting Name

Familial Amyloidosis Reflex

Useful For

Diagnosis of adult individuals suspected of having transthyretin-associated familial amyloidosis

Clinical Information

The amyloidoses are a group of diseases that result from the abnormal deposition of amyloid in various tissues of the body. They have been classified into 3 major types: primary, secondary, and hereditary. The most common form of amyloidosis (AL) is a disease of the bone marrow called primary systemic AL (immunoglobulin light chain). Secondary AL usually occurs in tandem with chronic infectious or inflammatory diseases, such as rheumatoid arthritis, tuberculosis, or osteomyelitis. Familial or hereditary AL is the least common form. Determining the specific type of AL is imperative in order to provide both an accurate prognosis and appropriate therapies.

 

Familial or hereditary transthyretin AL is an autosomal dominant disorder caused by variants in the transthyretin gene (TTR). The resulting amino acid substitutions lead to a relatively unstable, amyloidogenic transthyretin (TTR) protein. Most individuals begin to exhibit clinical symptoms between the third and seventh decades of life. Affected individuals may present with a variety of symptoms including sensorimotor and autonomic neuropathy, vitreous opacities, cardiomyopathy, nephropathy, and gastrointestinal dysfunction. TTR-associated AL is progressive over a course of 5 to 15 years and usually ends in death from cardiac or kidney failure or malnutrition. Orthotopic liver transplantation is a treatment option for some patients who are diagnosed in early stages of the disease. Other treatment options include the use of TTR tetramer stabilizer medications and gene-silencing therapies (RNA interference/RNAi) recently approved for use in several countries including the United States.

 

Mayo Clinic Laboratories recommends a testing strategy that includes both protein analysis by mass spectrometry (MS) and TTR gene analysis by DNA sequencing for patients in whom TTR-associated familial AL is suspected. The structure of TTR protein in plasma is first determined by MS. The presence of a disease-causing variant in the TTR gene leads to conformational changes in the TTR protein. This ultimately disrupts the stability of the mature TTR protein tetramer, leading to increased amounts of pro-amyloidogenic TTR monomers in the plasma of affected individuals. MS technology is able to identify the mass difference between wildtype TTR and variant TTR protein. Only the transthyretin (also known as prealbumin) is analyzed for amino acid substitutions. Other proteins involved in other less common forms of familial amyloidosis are not examined. If no alterations are detected, gene analysis will not be performed unless requested by the provider (ie, when the diagnosis is still strongly suspected; to rule out the possibility of a false-negative by MS). In all cases demonstrating a structural change by MS, DNA sequence analysis will be performed on the TTR gene to identify and characterize the observed alteration (disease-causing or benign variant). More than 90 variants that cause TTR-associated familial AL have now been identified within the TTR gene. Most of the variants described to date are single base pair changes that result in an amino acid substitution. Some of these variants correlate with the clinical presentation of AL.

 

For predictive testing in cases where a familial variant is known, testing for the specific variant by DNA sequence analysis (FMTT / Familial Mutation, Targeted Testing, Varies) is recommended. These assays do not detect alterations associated with non-TTR forms of familial AL. Therefore, it is important to first test an affected family member to determine if TTR is involved and to document a specific alteration in the family before testing at-risk individuals.

Interpretation

The presence of a structural change in transthyretin (TTR) is suggestive of a gene variant that requires confirmation by DNA sequence analysis. A negative result by mass spectrometry does not rule out a TTR variant. Mass spectrometric (MS) results are falsely negative if the amino acid substitution does not produce a measurable mass shift for the transthyretin variant. Approximately 90% of the TTR variants are positive by MS (see Cautions).

 

After identification of the variant at the DNA level, predictive testing for at-risk family members can be performed by molecular analysis (FMTT / Familial Mutation, Targeted Testing, Varies).

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
ATTRZ TTR Gene, Full Gene Analysis Yes No

Testing Algorithm

If familial amyloidosis by liquid chromatography-mass spectrometry is abnormal, DNA sequence will be performed and charged separately.

 

For more information, see Amyloidosis (Familial) Test Algorithm.

Report Available

3 to 9 days

Day(s) Performed

Tuesday

Clinical Reference

1. Sekijima Y: Hereditary transthyretin amyloidosis. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2001. Updated June 17, 2021 Accessed January 5, 2022. Available at www.ncbi.nlm.nih.gov/books/NBK1194/

2. Finsterer J, Iglseder S, Wanschitz J, et al: Hereditary transthyretin-related amyloidosis. Acta Neurol Scand. 2019 Feb;139(2):92-105

3. Sekijima Y. Transthyretin (ATTR) amyloidosis: clinical spectrum, molecular pathogenesis and disease-modifying treatments. J Neurol Neurosurg Psychiatry. 2015 Sep;86(9):1036-1043. doi: 10.1136/jnnp-2014-308724

Method Name

Affinity Chromatography/Mass Spectrometry (MS)

Specimen Type

Whole blood


Shipping Instructions


Specimen must arrive within 96 hours of collection.



Specimen Required


Container/Tube:

Preferred: Lavender top (EDTA)

Acceptable: Yellow top (ACD)

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send whole blood specimen in original tube. Do not aliquot.


Specimen Minimum Volume

0.5 mL

Specimen Stability Information

Specimen Type Temperature Time Special Container
Whole blood Refrigerated (preferred) 4 days
  Ambient  4 days

Reference Values

An interpretive report will be provided.

Test Classification

This test was developed, and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the US Food and Drug Administration.

CPT Code Information

82542

81404 (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
TTRX Familial Amyloidosis Reflex 94864-6

 

Result ID Test Result Name Result LOINC Value
22668 Wild Type Mass 94860-4
22669 Wild Type Width at Half Height 94863-8
22670 Second Mass 94862-0
22671 Mass Difference 94861-2
22673 Abnormal result 51968-6
50944 Interpretation 69047-9
50946 Reviewed By 18771-6

Forms

If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:

-Hematopathology/Cytogenetics Test Request (T726)

-Biochemical Genetics Test Request (T798)

Mayo Clinic Laboratories | Neurology Catalog Additional Information:

mml-Neuromuscular, mml-Autonomic